E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer Journal Article
| Authors: | Minikes, A. M.; Song, Y.; Feng, Y.; Yoon, C.; Yoon, S. S.; Jiang, X. |
| Article Title: | E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer |
| Abstract: | Gastric cancer is the third most common cause of cancer-related death worldwide. Diffuse-type gastric cancer (DGC) is a particularly aggressive subtype that is both difficult to detect and treat. DGC is distinguished by weak cell–cell cohesion, most often due to loss of the cell adhesion protein E-cadherin, a common occurrence in highly invasive, metastatic cancer cells. In this study, we demonstrate that loss-of-function mutation of E-cadherin in DGC cells results in their increased sensitivity to the non-apoptotic, iron-dependent form of cell death, ferroptosis. Homophilic contacts between E-cadherin molecules on adjacent cells suppress ferroptosis through activation of the Hippo pathway. Furthermore, single nucleotide mutations observed in DGC patients that ablate the homophilic binding capacity of E-cadherin reverse the ability of E-cadherin to suppress ferroptosis in both cell culture and xenograft models. Importantly, although E-cadherin loss in cancer cells is considered an essential event for epithelial-mesenchymal transition and subsequent metastasis, we found that circulating DGC cells lacking E-cadherin expression possess lower metastatic ability, due to their increased susceptibility to ferroptosis. Together, this study suggests that E-cadherin is a biomarker predicting the sensitivity to ferroptosis of DGC cells, both in primary tumor tissue and in circulation, thus guiding the usage of future ferroptosis-inducing therapeutics for the treatment of DGC. © 2023, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | controlled study; protein expression; human cell; genetics; missense mutation; mutation; nonhuman; binding affinity; biomarkers; biological marker; mouse; metastasis; animal experiment; animal model; genetic transcription; tumor xenograft; pathology; uvomorulin; cell culture; cell density; point mutation; site directed mutagenesis; cadherin; cadherins; loss of function mutation; stomach neoplasms; stomach tumor; epithelial mesenchymal transition; ferroptosis; humans; human; article; hippo signaling; yap signaling protein; diffuse-type gastric carcinoma |
| Journal Title: | Oncogene |
| Volume: | 42 |
| Issue: | 11 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-03-10 |
| Start Page: | 848 |
| End Page: | 857 |
| Language: | English |
| DOI: | 10.1038/s41388-023-02599-5 |
| PUBMED: | 36717701 |
| PROVIDER: | scopus |
| PMCID: | PMC10291936 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author Xuejun Jiang -- Source: Scopus |
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